Nasal delivery device

ABSTRACT

A breath-actuated nasal delivery device, comprising: a mouthpiece through which a user in use exhales to actuate the delivery device; a nosepiece for fitting to a nostril of the user through which a substance is in use delivered; a substance supply unit actuatable to deliver a dose of a substance through the nosepiece; a loading unit operable to load the substance supply unit with an actuation force; and a release mechanism for enabling actuation of the substance supply unit in response to exhalation by the user through the mouthpiece; wherein the release mechanism comprises a locking unit which is movable: between a locking configuration in which the substance supply unit is locked in a non-actuated position when loaded by the loading unit and a release configuration in which the substance supply unit is actuatable by the loading unit, and a trigger member for releasing the locking unit from the locking configuration to the release configuration in response to exhalation by the user through the mouthpiece and thereby enabling actuation of the substance supply unit.

The present invention relates to a breath-actuated nasal delivery devicefor and a method of delivering a substance, in particular one of aliquid, as a suspension or solution, or a powder containing amedicament, especially systemic or topical pharmaceuticals, or a vaccineto the nasal airway of a subject.

Referring to FIG. 1, the nasal airway 1 comprises the two nasal cavitiesseparated by the nasal septum, which airway 1 includes numerous ostia,such as the paranasal sinus ostia 3 and the tubal ostia 5, and olfactorycells, and is lined by the nasal mucosa. The nasal airway 1 cancommunicate with the nasopharynx 7, the oral cavity 9 and the lowerairway 11, with the nasal airway 1 being in selective communication withthe anterior region of the nasopharynx 7 and the oral cavity 9 byopening and closing of the oropharyngeal velum 13. The velum 13, whichis often referred to as the soft palate, is illustrated in solid line inthe closed position, as achieved by providing a certain positivepressure in the oral cavity 9, such as achieved on exhalation throughthe oral cavity 9, and in dashed line in the open position.

There are many nasal conditions which require treatment. One suchcondition is nasal inflammation, specifically rhinitis, which can beallergic or non-allergic and is often associated with infection andprevents normal nasal function. By way of example, allergic andnon-allergic inflammation of the nasal airway can typically effectbetween 10 and 20% of the population, with nasal congestion of theerectile tissues of the nasal concha, lacrimation, secretion of waterymucus, sneezing and itching being the most common symptoms. As will beunderstood, nasal congestion impedes nasal breathing and promotes oralbreathing, leading to snoring and sleep disturbance. Other nasalconditions include nasal polyps which arise from the paranasal sinuses,hypertrophic adenoids, secretory otitis media, sinus disease and reducedolfaction.

In the treatment of certain nasal conditions, the topical administrationof medicaments is preferable, particularly where the nasal mucosa is theprime pathological pathway, such as in treating or relieving nasalcongestion. Medicaments that are commonly topically delivered includedecongestants, anti-histamines, cromoglycates, steroids and antibiotics.At present, among the known anti-inflammatory pharmaceuticals, topicalsteroids have been shown to have an effect on nasal congestion. Topicaldecongestants have also been suggested for use in relieving nasalcongestion. The treatment of hypertrophic adenoids and chronic secretoryotitis media using topical decongestants, steroids and anti-microbialagents, although somewhat controversial, has also been proposed.Further, the topical administration of pharmaceuticals has been used totreat or at least relieve symptoms of inflammation in the anteriorregion of the nasopharynx, the paranasal sinuses and the auditory tubes.

Medicaments can also be systemically delivered through the nasalpathway, the nasal pathway offering a good administration route for thesystemic delivery of pharmaceuticals, such as hormones, for example,oxytocin and calcitionin, and analgetics, such as anti-migrainecompositions, as the high blood flow and large surface area of the nasalmucosa advantageously provides for rapid systemic uptake.

Nasal delivery is also expected to be advantageous for theadministration of medicaments requiring a rapid onset of action, forexample, analgetics, anti-emetics, insulin, anti-epileptics, sedativesand hypnotica, and other pharmaceuticals, for example, cardio-vasculardrugs. It is envisaged that nasal administration will provide for a fastonset of action, at a rate similar to that of injection and at a ratemuch faster than that of oral administration. Indeed, for the treatmentof many acute conditions, nasal administration is advantageous over oraladministration, since gastric stasis can further slow the onset ofaction following oral administration.

It is also expected that nasal delivery could provide an effectivedelivery route for the administration of proteins and peptides asproduced by modem biotechnological techniques. For such substances, themetabolism in the intestines and the first-pass-effect in the liverrepresent significant obstacles for reliable and cost-efficientdelivery.

Furthermore, it is expected that nasal delivery using the nasal deliverytechnique of the present invention will prove effective in the treatmentof many common neurological diseases, such as Alzheimer's, Parkinson's,psychiatric diseases and intracerebral infections, where not possibleusing existing techniques. The nasal delivery technique of the presentinvention allows for delivery to the olfactory region, which region islocated in the superior region of the nasal cavities and represents theonly region where it is possible to circumvent the blood-to-brainbarrier (BBB) and enable communication with the cerebrospinal fluid(CSF) and the brain.

Also, it is expected that the nasal delivery technique of the presentinvention will allow for the effective delivery of vaccines.

Aside from the delivery of medicaments, the irrigation of the nasalmucosa with liquids, in particular saline solutions, is commonlypracticed to remove particles and secretions, as well as to improve themucociliary activity of the nasal mucosa. These solutions can be used incombination with active pharmaceuticals.

For any kind of drug delivery, accurate and reliable dosing isessential, but it is of particular importance in relation to theadministration of potent drugs which have a narrow therapeutic window,drugs with potentially serious adverse affects and drugs for thetreatment of serious and life-threatening conditions. For someconditions, it is essential to individualize the dosage to theparticular situation, for example, in the case of diabetes mellitus. Fordiabetes, and, indeed, for many other conditions, the dosage of thepharmaceutical is preferably based on actual real-time measurements.Currently, blood samples are most frequently used, but the analysis ofmolecules in the exhalation breath of subjects has been proposed as analternative to blood analysis for several conditions. Breath analysis iscurrently used for the diagnosis of conditions such as helicobacterpylori infections which cause gastric ulcers.

To date, nasal medicaments have been primarily delivered as drops or bymechanical nasal spray pumps. With mechanical spray pumps, the meanparticle size is typically between 40 μm and 80 μm in order to preventthe inhalation of delivered particles. In general, particles smallerthan 10 μm will bypass the nose and can be inhaled. Indeed, the new FDAguidelines require that the fraction of particles less than 10 μm be atmost 5%.

Whilst the provision of a spray having a larger mean particle sizeprevents the inhalation of the particles, these larger particles are notoptimal for achieving a good distribution to the nasal mucosa.

The applicant has now recognized that the closure of the oropharyngealvelum during the delivery of a substance to the nasal airway preventsthe possible inhalation of the substance, thereby enabling the deliveryof an aerosol having a much smaller mean particle size than achieved bytraditional nasal spray pumps. In this way, an aerosol can be generatedwhich has an optimal particle size distribution.

A further advantage is that the nosepiece acts to expand the narrowest,anterior part of the nasal cavity and thereby reduces the unwanted highdeposition in the anterior region of the nasal cavity which is lined bysquamous epithelium.

In addition, the applicant has recognized that, by establishing abi-directional flow through the nasal cavities as described inWO-A-00/51672, that is, an air flow which passes into one nostril,around the posterior margin of the nasal septum and in the oppositedirection out of the other nostril, an aerosol having an optimal flowrate and timing can be generated. Furthermore, the bi-directional airflow advantageously acts to stimulate the sensory nerves in the nasalmucosa, thereby conditioning the subject for the delivery and providinga more comfortable delivery situation.

A yet further advantage is that the air flow acts to create a positivepressure inside the nasal passages connected in series, which tends toexpand and widen narrow and congested regions.

A still yet further advantage is that the two-point fixation of thedevice in the nose with a well-fitting nozzle and in the mouth providesa much more stable and reproducible positioning of the device ascompared to traditional spray pumps. Thus, in addition to improveddeposition and reproducibility, the new concept provides a moreuser-friendly and intuitive nasal delivery method.

Furthermore, the delivery device, in being pre-primed and actuatable bythe oral exhalation breath of a subject, does not require theapplication of an actuation force by the subject at the time ofactuation. Traditionally, mechanical liquid delivery pumps are operatedby the manual compression of a chamber containing a volume of liquid toexpel a flow of a metered volume of liquid, and mechanical powderdelivery pumps are operated by the manual compression of a chambercontaining a volume of air to drive and expel a flow of a metered amountof a dry powder. Such operation requires a relatively high actuationforce, typically of the order of 50 N, which high force often leads tosignificant movement of the delivery device, it being very difficult tomaintain a delivery device stationary when attempting to apply a highactuation force. Movement of the delivery device, both in thepositioning and orientation of the nozzle, will lead to poorreproducibility, dose accuracy and patient compliance. In beingpre-primed and actuatable by the oral exhalation breath of a subject,the delivery device of the present invention overcomes this problem.

In addition, by not requiring a subject to apply an actuation force atthe instance of delivery, the delivery device provides for the sameactuation force in each delivery, and also provides for delivery at anoptimal pressure and/or flow rate, and the delivery of substance havingan optimized particle size distribution.

Yet furthermore, in providing for the closure of the oropharyngeal velumof a subject, substance is prevented from entering the lower airway, andalso, in a preferred embodiment, bi-directional delivery can be achievedthrough the nasal cavities.

It will be appreciated that the nasal delivery devices of the presentinvention are quite different to inhalation devices which provide forinhalation into the lower airway.

Inhalation devices have been used for a long time for the inhalation ofmedicaments in the treatment of lower airway pathologies.

One such inhalation device is the pressurized metered dose inhaler(pMDI). In such inhalers, a metered dose of medicament is released as anaerosol by actuating an aerosol canister, with the particle sizes of theaerosol being required to be small, typically less than 5 μm, in orderto reach the distal parts of the lower airway. One drawback withtraditional pMDIs is that the subject must co-ordinate inhalation withthe aerosol release in order to deliver the aerosolized medicamenteffectively to the lower airway. Inadequate co-ordination represents aconsiderable problem, significantly reducing both lung deposition andreproducibility. Another drawback with traditional pMDIs is the use ofchlorine-containing compounds as the propellant gas, as such gases arenot environmentally friendly and have been demonstrated to destroy theozone layer. Recently, in order to alleviate these drawbacks, pMDIs havebeen developed which use an alternative propellant gas, this being ahydrofluoroalkane (HFA), and incorporate a breath-actuation mechanismwhich provides for actuation of the aerosol canister on inhalation bythe subject.

Another such inhalation device is the dry powder inhaler, such as theTurbohaler® inhaler as supplied by AstraZeneca and the Discus® inhaleras supplied by GSK. These dry powder inhalers do not requireco-ordination of delivery and inhalation and can improve deposition tothe lower airways.

Bi-directional nasal drug delivery is achieved by directing an exhaledair flow through the nasal passages in series, or by triggering anotherflow source to create such an air flow, whereas breath actuation ofpulmonary drug delivery is by inhalation into a closed expanding volume,that is, the lungs. For bi-directional nasal delivery, it is desirableto establish the air flow before the drug is released, whereas forinhalation, the release is best achieved at the very beginning ofinspiration to reach the most distal parts of the lungs.

Increased airway resistance in pathological conditions, both in thepulmonary and nasal airways, is a challenge. In inhalation devices, anair flow is created by the inspiratory muscles creating a negativepressure inside the chest. In this way, air is sucked through the deviceand into the airways. For pulmonary drug delivery, it is essential thatthe triggering occurs, not only early, but also at a relatively low flowto ensure release in subjects with a very low lung capacity.Furthermore, the releasing action should require as little energy aspossible, as any resistance in the device will impede free inhalation.Still most subjects, even patients with lung diseases, will be able toachieve a flow rate of 25 L/min which is typically required to triggerthe release from a pMDI device.

For the nose, the situation is more complex and in many ways different.The expiratory muscles in the thorax produce the exhaled air flow usedto trigger release, and this air flow is then directed through thedevice and into the nasal passages in series, or used to trigger anotherflow source. Thus, the triggering air flow is completely reversed ascompared to pulmonary breath actuation, and the air flow is directedinto another airway/compartment separated from the lower airways.

Furthermore, the nose geometry is designed to humidify, warm and filterthe inspired air to protect the lower airways. The resistance in thenose alone equals 50% of the total airway resistance, and the resistancemay increase immensely when congested. Owing to the high anteriorresistance, turbulence occurs just posterior to the constriction,increasing deposition in this region. To achieve a better distributionto larger and more posterior parts of the nasal mucosa, it is envisagedto be advantageous to have the drug released at a lower flow in acongested nose and at a higher flow in a open nose. This requires asystem which can be released not only by flow, but also by pressure.Such release is essential for an efficient and reliableexhalation-triggered nasal drug delivery. In this regard, reference ismade to co-pending UK application nos 0104692.9 and 0114272.8, thecontents of which are hereby incorporated by reference. The two maintriggering modes, flow and pressure, are to certain extent overlapping.They can be incorporated in one single mechanism or provided as separatemechanisms. However, the nose may become completely blocked, inparticular during colds and allergic attacks. In this situation, itbecomes impossible to establish a bi-directional air flow, but still itis desirable and necessary to deliver drugs to the nose. Furthermore,for some purposes, the exhaled air flow may only be used to triggerrelease from a pMDI or a mechanical spray pump. Again, the triggeringmay be mainly flow dependent or mainly/strictly pressure dependent.

Thus, the requirements for a breath-actuation mechanism for nasal drugsare different from those for inhaled drugs. The main features ofexhalation-triggered nasal drug release are (i) triggering of drugrelease by exhalation, (ii) triggering when a bi-directional flow isestablished, (iii) triggering at a flow rate which provides optimaldistribution, (iv) triggering in a very congested and even completelyblocked nose, (v) triggering of external flow sources (pMDI), and (vii)triggering of a spray pump aerosol even in the absence of bi-directionalflow.

In one aspect the present invention provides a breath-actuated nasaldelivery device, comprising: a mouthpiece through which a user in useexhales to actuate the delivery device; a nosepiece for fitting to anostril of the user through which a substance is in use delivered; asubstance supply unit actuatable to deliver a dose of a substancethrough the nosepiece; a loading unit operable to load the substancesupply unit with an actuation force; and a release mechanism forenabling actuation of the substance supply unit in response toexhalation by the user through the mouthpiece; wherein the releasemechanism comprises a locking unit which is movable between a lockingconfiguration in which the substance supply unit is locked in anon-actuated position when loaded by the loading unit and a releaseconfiguration in which the substance supply unit is actuatable by theloading unit, and a trigger member for releasing the locking unit fromthe locking configuration to the release configuration in response toexhalation by the user through the mouthpiece and thereby enablingactuation of the substance supply unit.

In one embodiment the trigger member comprises a flow-sensitive elementin fluid communication with the mouthpiece.

In one embodiment the flow-sensitive element comprises a vane.

Preferably, the flow-sensitive element includes an aperture which allowsfor a predeterminable air flow thereover prior to actuation.

Preferably, the flow-sensitive element is one or both of shaped andsized such as to allow for a predeterminable air flow thereover prior toactuation.

In another embodiment the trigger member comprises a pressure-sensitiveelement in fluid communication with the mouthpiece.

In one embodiment the pressure-sensitive element comprises a vane.

In another embodiment the pressure-sensitive element comprises aflexible membrane.

Preferably, the flexible membrane comprises a resilient membrane.

In a further embodiment the pressure-sensitive element comprises aflexible membrane in fluid communication with the mouthpiece and a vaneoperable by the flexible membrane.

Preferably, the flexible membrane comprises a resilient membrane.

Preferably, the delivery device further comprises: a pressure-sensitivesealing unit disposed downstream of the trigger member and beingoperable to vent an air flow developed by the user on exhalation throughthe mouthpiece to atmosphere, the sealing unit being normally closed andoperable such as to be opened on generation of a predeterminablepressure thereat.

In one embodiment the sealing unit comprises an annular seal, a sealingmember movable between a closed position in sealing engagement with theannular seal and an open position in which an air flow can flow throughthe annular seal, and a biasing element for normally biasing the sealingmember to the closed position and enabling the sealing member to beopened on generation of a predeterminable pressure thereat.

In another embodiment the sealing unit comprises a flexible membranewhich is movable between a closed position and an open position in whichan air flow can flow thereby.

Preferably, the flexible membrane comprises a resilient membrane.

Preferably, the trigger member includes a pivot pin about which the sameis rotatable, which pivot pin is engaged by the locking unit when in thelocking configuration such that the locking unit is moved from thelocking configuration to the release configuration on rotation of thepivot pin.

More preferably, the locking unit includes a first, support member whichabuts the substance supply unit in the locking configuration and asecond, link member which engages the pivot pin of the trigger member inthe locking configuration, wherein the link member is movable inrelation to the support member and configured to be moved on rotation ofthe pivot pin to move the locking unit from the locking configuration tothe release configuration.

Yet more preferably, the link member is rotatably connected to thesupport member.

Still more preferably, the link member is configured to load the pivotpin radially.

In one embodiment the delivery device further comprises: a flow pathfluidly connecting the nosepiece and the mouthpiece, whereby an air flowdeveloped by exhalation by the user through the mouthpiece is deliveredthrough the nosepiece.

In another embodiment the nosepiece and the mouthpiece are fluidlyisolated such that an air flow developed by exhalation by the userthrough the mouthpiece is not delivered through the nosepiece.

In one embodiment the substance supply unit comprises a nebulizer forsupplying an aerosol.

In another embodiment the substance supply unit comprises an aerosolcanister for supplying an aerosol.

In a further embodiment the substance supply unit comprises a deliverypump unit for supplying one of an aerosol or a jet.

In one preferred embodiment the delivery pump unit comprises a liquidpump unit for supplying a liquid aerosol.

In another preferred embodiment the delivery pump unit comprises apowder pump unit for supplying a powder aerosol.

In a yet further embodiment the substance supply unit comprises a powderdelivery unit for delivering a powder aerosol.

Preferably, the delivery device further comprises: a flow-controlmechanism disposed upstream of the trigger member to at least restrictan air flow to the trigger member such as to prevent actuation of therelease mechanism on exhalation by the user through the mouthpiece wherethe delivery device is being improperly operated.

In one embodiment the flow-control mechanism is configured to at leastrestrict the air flow to the trigger member where the delivery device isin an improper orient.

In another embodiment the flow-control mechanism is configured to atleast restrict the air flow to the trigger member where the air flowdeveloped by the user has a rate exceeding a predeterminable thresholdvalue.

More preferably, the flow-control mechanism comprises a flow channelsection which includes a recess, and a ball which is movably, captivelydisposed within the flow channel section, the ball normally, with properoperation of the delivery device, resting in the recess such as to allowa sufficient air flow to the trigger member as to enable actuation ofthe release mechanism, and being moved to at least partially block theflow channel section where the delivery device is being improperlyoperated such as to prevent actuation of the release mechanism.

In another aspect the present invention provides a breath-actuated nasaldelivery device, comprising: a mouthpiece through which a user in useexhales to actuate the delivery device; a nosepiece for fitting to anostril of the user through which a substance is in use delivered andbeing in fluid communication with the mouthpiece; a substance supplyunit actuatable to deliver a dose of a substance through the nosepiece;a release mechanism for enabling actuation of the substance supply unitin response to exhalation by the user through the mouthpiece; and aflow-control mechanism disposed upstream of the trigger member to atleast restrict an air flow to the trigger member such as to preventactuation of the release mechanism on exhalation by the user through themouthpiece where the delivery device is being improperly operated.

In one embodiment the flow-control mechanism is configured to at leastrestrict the air flow to the trigger member where the delivery device isin an improper orient.

In another embodiment the flow-control mechanism is configured to atleast restrict the air flow to the trigger member where the air flowdeveloped by the user has a rate exceeding a predeterminable thresholdvalue.

Preferably, the flow-control mechanism comprises a flow channel sectionwhich includes a recess, and a ball which is movably, captively disposedwithin the flow channel section, the ball normally, with properoperation of the delivery device, resting in the recess such as to allowa sufficient air flow to the trigger member as to enable actuation ofthe release mechanism, and being moved to at least partially block theflow channel section where the delivery device is being improperlyoperated such as to prevent actuation of the release mechanism.

In a further aspect the present invention provides a release mechanismfor enabling actuation of a substance supply unit, the release mechanismcomprising: a locking unit which is movable between a lockingconfiguration in which the substance supply unit is locked in anon-actuated position and a release configuration in which the substancesupply unit is actuatable; and a trigger member for releasing thelocking unit from the locking configuration to the release configurationin response to a gas flow thereat, wherein the trigger member includes apivot pin about which the same is rotatable, which pivot pin is engagedby the locking unit when in the locking configuration such that thelocking unit is moved from the locking configuration to the releaseconfiguration on rotation of the pivot pin.

Preferably, the locking unit includes a first, support member whichabuts the substance supply unit in the locking configuration and asecond, link member which engages the pivot pin of the trigger member inthe locking configuration, wherein the link member is movable inrelation to the support member and configured to be moved on rotation ofthe pivot pin to move the locking unit from the locking configuration tothe release configuration.

Preferably, the link member is rotatably connected to the supportmember.

Preferably, the link member is configured to load the pivot pinradially.

In a still further aspect the present invention provides abreath-actuated nasal delivery pump for delivering a liquid containing asubstance to a nasal cavity of a user.

In one embodiment the delivery pump is a spray pump and the liquid isdelivered as a liquid spray.

In another embodiment the delivery pump is a jet pump and the liquid isdelivered as a liquid jet.

Preferred embodiments of the present invention will now be describedhereinbelow by way of example only with reference to the accompanyingdrawings, in which:

FIG. 1 schematically illustrates the anatomy of the upper respiratorytract of a human subject;

FIG. 2( a) illustrates a perspective view of a nasal delivery device inaccordance with a first embodiment of the present invention;

FIG. 2( b) illustrates one side view of the nasal delivery device ofFIG. 2( a);

FIG. 2( c) illustrates another side view of the nasal delivery device ofFIG. 2( a);

FIG. 2( d) illustrates a plan view of the nasal delivery device of FIG.2( a);

FIG. 3 illustrates a part-exploded perspective view of the nasaldelivery device of FIG. 2( a);

FIG. 4( a) illustrates one side view of the substance delivery assemblyof the nasal delivery device of FIG. 2( a);

FIG. 4( b) illustrates another side view of the substance deliveryassembly of the nasal delivery device of FIG. 2( a);

FIG. 4( c) illustrates a part-sectional other side view of the substancedelivery assembly of the nasal delivery device of FIG. 2( a);

FIG. 4( d) illustrates an exploded perspective view of the substancedelivery assembly of the nasal delivery device of FIG. 2( a);

FIG. 5( a) illustrates a side view of the loading unit of the loadingmechanism of the substance delivery assembly of the nasal deliverydevice of FIG. 2( a);

FIG. 5( b) illustrates a vertical sectional view through the loadingunit of FIG. 5( a);

FIG. 5( c) illustrates an exploded side view of the loading unit of FIG.5( a);

FIG. 6( a) illustrates a side view of the pressure-sensitive releasemechanism of the nasal delivery device of FIG. 2( a);

FIG. 6( b) illustrates a vertical sectional view of thepressure-sensitive release mechanism of FIG. 6( a);

FIG. 6( c) illustrates an exploded perspective view of thepressure-sensitive release mechanism of FIG. 6( a);

FIG. 7( a) illustrates a part cut-away perspective view of the nasaldelivery device of FIG. 2( a) in an inoperative, rest configuration;

FIG. 7( b) illustrates a part cut-away perspective view of the nasaldelivery device of FIG. 2( a) in a loaded, operable configuration;

FIG. 7( c) illustrates a part cut-away perspective view of the nasaldelivery device of FIG. 2( a) where operated in one mode of operation;

FIG. 7( d) illustrates a part cut-away perspective view of the nasaldelivery device of FIG. 2( a) where operated in another mode ofoperation;

FIG. 8( a) illustrates a part-sectional view of a nasal delivery devicein accordance with a second embodiment of the present invention,illustrated in an inoperative, rest configuration;

FIG. 8( b) illustrates a part-sectional view of the nasal deliverydevice of FIG. 8( a) in a loaded, operable configuration;

FIG. 8( c) illustrates a part-sectional view of the nasal deliverydevice of FIG. 8( a) in an actuated configuration;

FIG. 9( a) illustrates in enlarged scale region A of FIG. 8( a);

FIG. 9( b) illustrates in enlarged scale region B of FIG. 8( c);

FIG. 10( a) illustrates a part-sectional view of a nasal delivery devicein accordance with a third embodiment of the present invention,illustrated in an inoperative, rest configuration;

FIG. 10( b) illustrates a part-sectional view of the nasal deliverydevice of FIG. 10( a) in a loaded, operable configuration;

FIG. 10( c) illustrates a part-sectional view of the nasal deliverydevice of FIG. 10( a) in an actuated configuration;

FIG. 11( a) illustrates in enlarged scale region C of FIG. 10( a);

FIG. 11( b) illustrates in enlarged scale region D of FIG. 10( c);

FIG. 12( a) illustrates a part-sectional view of a nasal delivery devicein accordance with a fourth embodiment of the present invention,illustrated in an inoperative, rest configuration;

FIG. 12( b) illustrates a part-sectional view of the nasal deliverydevice of FIG. 12( a) in a loaded, operable configuration;

FIG. 12( c) illustrates a part-sectional view of the nasal deliverydevice of FIG. 12( a) in an actuated configuration;

FIG. 13( a) illustrates in enlarged scale region E of FIG. 12( a);

FIG. 13( b) illustrates in enlarged scale region F of FIG. 12( c);

FIGS. 14( a) and (b) illustrate a flow-control mechanism in accordancewith an embodiment of the present invention; and

FIGS. 15( a) to (c) illustrate the function of the flow-controlmechanism of FIGS. 14( aand (b) where a user exhales rapidly or inhalestherethrough.

FIGS. 2 to 7 illustrate a breath-actuated nasal delivery device inaccordance with a first embodiment of the present invention.

The delivery device comprises a housing unit 14, in this embodimentprovided by first and second housing parts 14 a, 14 b, which defines amain body 15 which is typically gripped in the hand of a user, anosepiece 17 for fitting to a nostril of a user and a mouthpiece 19through which the user exhales to actuate the delivery device, and aguide member 20 which, in this embodiment, together with the housingunit 14 defines a main flow path 21 between the nosepiece 17 and themouthpiece 19.

The main body 15 includes first and second cam recesses 22, 22 onopposed sides at a lower end thereof for receiving respective ones ofthe engagement elements 55, 55 of a loading member 51, as will bedescribed in more detail hereinbelow. The cam recesses 22, 22 eachcomprise a cam surface 23 which engages the cam element 57 of arespective one of the engagement elements 55, 55 of the loading member51, and a lug aperture 24 adjacent the cam surface 23 through whichextends the lug 58 of the respective one of the engagement elements 55,55 of the loading member 51.

The main body 15 includes at least one external venting aperture, inthis embodiment a plurality of external venting apertures 25, 25 whichprovide for a vent to atmosphere, and further defines a gas venting path26 which can provide a fluid communication path between the externalventing apertures 25, 25 and the main flow path 21 at a locationdownstream of the vane 89 of a trigger member 61, as will be describedin more detail hereinbelow. As will be described in more detailhereinbelow, the gas venting path 26 is normally isolated from the mainflow path 21 by a pressure-sensitive sealing unit 93, and is broughtinto fluid communication with the main flow path 21 by opening thepressure-sensitive sealing unit 93 where a sufficient flow rate cannotbe developed through the main flow path 21, for example, as a result ofthe nasal passage of the user being congested, and the pressure in themain flow path 21 exceeds a predetermined threshold pressure.

In this embodiment the nosepiece 17 has a tapering section which narrowsto the distal end thereof and acts, when inserted, typically from about1 to 2 cm, into the anterior part of a nasal cavity, to expand thenarrow nasal valve of the nasal cavity and provide a fluid-tight seal.

In this embodiment the mouthpiece 19 is configured to be gripped in thelips of a user. In an alternative embodiment the mouthpiece 19 could beconfigured to be gripped by the teeth of a user and sealed by the lipsof the user. In a preferred embodiment the mouthpiece 19 is specificallyconfigured to have one or both of a shape and geometry which allows thedelivery device to be gripped repeatedly in the same position, therebyproviding for the nosepiece 17 to be reliably inserted in the sameposition in the nasal cavity.

The guide member 20 includes an arcuate section 27, adjacent which thedistal end of the vane 89 of the trigger member 61 is movably disposed,and a vane stop 29 which defines the rest position of the vane 89 of thetrigger member 61 when a locking assembly 59 is in the lockingconfiguration. The provision of the vane stop 29 acts to prevent theactuation of a substance supply unit 31 on inhalation by the user, aswill be described in more detail hereinbelow.

In this embodiment the main flow path 21 provides a fluid communicationpath between the nosepiece 17 and the mouthpiece 19 such that anexhalation breath of the user can provide for bi-directional flowthrough the nasal cavities as disclosed in WO-A-00/51672. In alternativeembodiments there could be no fluid communication path between thenosepiece 17 and the mouthpiece 19 such that an exhalation breath of theuser is not directed to the nasal cavities of the user. Thesealternative embodiments include those where substance is delivered in aseparate gas flow, such as from a pressurized canister, for example, apMDI canister.

The delivery device further comprises a breath-actuated substancedelivery assembly 30 for delivering substance through the nosepiece 17on exhalation by the user through the mouthpiece 19.

The substance delivery assembly 30 comprises a substance supply unit 31for delivering a metered dose of a substance on actuation of the same,an outlet unit 32 which is fluidly connected to the substance supplyunit 31 for delivering substance through the nosepiece 17, a loadingmechanism 33 for loading the substance supply unit 31, and a releasemechanism 34 for releasing the substance supply unit 31 from a loaded,non-actuated position to an actuated position on exhalation by the userthrough the mouthpiece 19.

In this embodiment the substance supply unit 31, as a mechanical pump,comprises a container 35 containing a volume of liquid containing asubstance, a pump fitting 36 which includes a metering chamber and isconnected to the container 35, and an outlet stem 37 which is movablydisposed to the pump fitting 36 and through which liquid is delivered.In operation, a metered volume of liquid is delivered on relativemovement of the pump fitting 36 and the outlet stem 37, in thisembodiment movement of the pump fitting 36 in relation to the outletstem 37, between a first position in which the outlet stem 37 isextended from the pump fitting 36 and a second position in which theoutlet stem 37 is depressed into the pump fitting 36.

In this embodiment the substance supply unit 31 is a multi-dose devicefor enabling the delivery of a succession of metered doses of substance.In an alternative embodiment the substance supply unit 31 could be asingle dose device for delivering a single metered dose of substance.

The outlet unit 32 comprises an outlet block 40 which is fluidlyconnected to the outlet stem 37 of the substance supply unit 31 and, inthis embodiment, includes a valve and swirl chamber, and a delivery tube41 from which a mist of fine droplets of the liquid is expelled onactuation of the substance supply unit 31. In an alternative embodimentthe delivery tube 41 could be configured to provide for the delivery ofa liquid jet.

The loading mechanism 33 comprises a loading unit 42 which comprises abiasing element 43, in this embodiment a resilient element, here acompression spring, and first and second retaining elements 44, 45between which the biasing element 43 is disposed such as to loadablewith an actuation force, which is sufficient to actuate the substancesupply unit 31 when released, on compression of the same, in thisembodiment by moving one, the lower, retaining element 44 relative tothe other, upper, retaining element 45. In this embodiment the retainingelements 44, 45 are coupled by a link 47, here a nut and bolt, toconstrain the expansion of the biasing element 43 and thereby pre-biasthe biasing element 43 to a predetermined extent. In this embodiment theone, lower retaining element 44 includes first and second shoulders 49,49 on opposed sides thereof which are engaged by the respective lugs 58,58 of the engagement elements 55, 55 of the loading member 51, as willbe described in more detail hereinbelow.

The loading mechanism 33 further comprises a loading member 51 forloading the loading unit 42. In this embodiment the loading member 51comprises a U-shaped lever 53 which is movable from a non-loadingposition, as illustrated in FIG. 7( a), to a loading position, asillustrated in FIG. 7( b), in which the loading member 51 acts to loadthe loading unit 42 by biasing the same against the bottom end of thecontainer 35 of the substance supply unit 31.

The loading member 51 includes first and second engagement elements 55,55 which are disposed in opposed relation at the respective ends of thelever 53 and are located in t o respective ones of the cam recesses 22,22 in the main body 15 of the body unit 14 and engage respective ones ofthe shoulders 49, 49 on the lower retaining element 44 of the loadingunit 42.

The engagement elements 55, 55 each comprise a cam 57 which is locatedat a respective one of the cam surfaces 23, 23 of the cam recesses 22,22 in the main body 15 of the body unit 14, and a lug 58 which extendsthrough a respective one of the lug apertures 24, 24 of the cam recesses22, 22 in the main body 15 of the body unit 14 and engages a respectiveone of the shoulders 49, 49 on the lower retaining element 44 of theloading unit 42. The cams 57, 57 are configured such that, on moving thelever 53 from the non-loading, rest position to the loading position,the lugs 58, 58 are driven, in this embodiment upwards, towards thelower retaining element 44 of the loading unit 42 such as to move thelower retaining element 44 of the loading unit 42 relative to the upperretaining element 45 of the loading unit 42 which is constrained by thebottom end of the container 35 of the substance supply unit 31, andthereby load the loading unit 42.

The release mechanism 34 comprises a locking assembly 59 which acts tolock the substance supply unit 31 in the non-actuated position, in thisembodiment by preventing movement of the pump fitting 36 relative to theoutlet stem 37 of the substance supply unit 31, until actuation of therelease mechanism 34, and a trigger member 61 which is coupled to thelocking assembly 59 and disposed at the mouthpiece 19 such as to supportthe locking assembly 59 until acted upon by an oral exhalation breath ofa user.

In this embodiment the locking assembly 59 comprises a body member 62which is fixed to the outlet block 40 of the outlet unit 32, a first,support member 63, which is hinged, in this embodiment about a hingeaxis 64 to the body member 62, and engages the pump fitting 36 of thesubstance supply unit 31 in the locked position, a second, link member65 which is hinged about a hinge axis 66 to the support member 63between a first, locking position and a second, release position, andcouples the support member 63 to the trigger member 61 when loaded, afirst biasing element 67, in this embodiment a resilient element, here atension spring, which is coupled to the body member 62 and the supportmember 63 such as to bias the support member 63 to the locking position,and a second biasing element 69, in this embodiment a resilient element,here compression springs, which is coupled to the support member 63 andthe link member 65 such as to bias the link member 65 to the lockingposition.

In this embodiment the body member 62 includes a support member stop 70which defines the locking position of the support member 63 where thesupport member 63 is biased to the locking position.

In this embodiment the hinge axis 64 of the support member 63 is offsetfrom the longitudinal axis of the substance supply unit 31, such that,on release of the link member 65 from the locking position, the supportmember 63 is hinged upwardly by the action of the substance supply unit31 being driven upwardly by the loading unit 42.

In this embodiment the support member 63 comprises first and second arms73, 75 which extend in opposite directions and define an abutmentsurface 77 at the junction therebetween, and, with the support member 63in the locking position, the abutment surface 77 engages the upper endof the pump fitting 36 of the substance supply unit 31, the first arm 73extends over the upper end of the pump fitting 36 in a directionsubstantially orthogonal to the longitudinal axis of the substancesupply unit 31 and the second arm 75 is inclined upwardly such as toengage the support member stop 70 on the body member 62.

In this embodiment the first arm 73 of the support member 63 includes afirst link member stop 79 against which the link member 65 is biased inthe locking position, with the first link member stop 79 beingconfigured such that the link member 65 extends substantiallyorthogonally to the first arm 73 of the support member 63, and parallelto the longitudinal axis of the substance supply unit 31, when in thelocking position.

In this embodiment the first arm 73 of the support member 63 includes asecond link member stop 81 which acts to limit the rotation of the linkmember 65 when released from the locking position.

In this embodiment the link member 65 is a substantially rigid memberwhich includes at least one, in this embodiment first and secondengagement elements 83, 83 which engage the trigger member 61 when thelink member 65 is in the locking position. In this embodiment theengagement elements 83, 83 each include an end cap 85 which is formed ofa material of a high coefficient of friction, such as a rubber material,to provide for controlled engagement with the trigger member 61, andthereby prevent uncontrolled slipping from the trigger member 61. In analternative embodiment the link member 65 could comprise a flexible,preferably resilient, element.

In this embodiment the trigger member 61 comprises a pivot pin 87 aboutwhich the trigger member 61 is rotatable between a first, supportingposition in which the trigger member 61 engages the link member 65 inthe locked position, and a second, released position in which the linkmember 65 is not supported, in having been caused to roll off the pivotpin 87, and released from the locking position.

In this embodiment the trigger member 61 further comprises aflow-sensitive vane 89 which extends from the pivot pin 87 andsubstantially closes the main flow path 21 when in the supportingposition. In this embodiment the vane 89 is configured to engage thevane stop 29 on the arcuate section 27 of the guide member 20 when inthe supporting position. In this embodiment the vane 89 includes anaperture 90 which acts to require a predetermined air flow through themain flow path 21 prior to releasing the trigger member 61 from thesupporting position. Advantageously, with this configuration, abi-directional air flow can be achieved through the nasal cavities priorto release of substance through the nosepiece 17. In an alternativeembodiment, an air flow can be provided through the main flow path 21prior to releasing the trigger member 61 from the supporting position bysizing the vane 89 to be of a size slightly smaller than the section ofthe main flow path 21, whereby an air flow of up to a predetermined flowrate can be developed about the vane 89 prior to driving the vane 89such as to cause the trigger member 61 to be released from thesupporting position.

The delivery device further comprises a pressure-sensitive sealing unit93 which is configured normally to be closed, and thereby isolate thegas venting path 26 from the main flow path 21, such that the exhaledair flow of a user is directed through the main flow path 21, and beopened where the pressure in the main flow path 21 exceeds apredetermined threshold pressure such that an air flow can be developedover the vane 89 of the trigger member 61 which has a sufficient flowrate as to drive the vane 89 to actuate the locking assembly 59, withthe exhaled air flow being vented through the external venting apertures25, 25. As mentioned hereinabove, this configuration enables actuationof the release mechanism 34 in the event that the nasal passage of theuser is so congested as to prevent the attainment of a sufficient flowrate as to drive the vane 89 of the trigger member 61 to actuate therelease mechanism 34.

In this embodiment the sealing unit 93 comprises an annular seal 95which is disposed such as to be a sealing fit at one, the upstream, endof the gas venting path 26, a sealing member 97 which is movable betweena first, normally closed position and a second, open position, and abiasing element 99, in this embodiment a resilient element, here acompression spring, for biasing the sealing member 97 to the closedposition. The sealing member 97 includes an annular seat 101 and ismovable between the closed position in which the annular seat 101 is insealing engagement with the annular seal 95, with the annular seat 101being maintained in sealing engagement with the annular seal 95 by thebiasing element 99, and thereby closes the sealing unit 93 to isolatethe gas venting path 26 from the main flow path 21, and the openposition in which the sealing member 97 is driven out of sealingengagement with the annular seal 95 by the generation of a predeterminedventing pressure in the main flow path 21, with the force generated bythe venting pressure exceeding the biasing force applied by the biasingelement 99, and thereby providing for fluid communication between themain flow path 21 and the gas venting path 26 such as to enable an airflow to be developed over the vane 89 of the trigger member 61 asrequired to actuate the release mechanism 34.

Operation of the delivery device will now be described hereinbelow.

In operation, a user first takes the device, as illustrated in FIG. 7(a), and primes the device by rotating the loading member 51 of theloading mechanism 33 to the loaded position, as illustrated in FIG. 7(b). With the release mechanism 34 in the locked configuration, that is,with the abutment surface 77 of the supporting member 73 of the lockingassembly 59 abutting the pump fitting 36, the loading unit 42 is biasedagainst the bottom of the container 35 of the substance supply unit 31.The user then inserts the nosepiece 17 into one of the nasal cavities,grips the mouthpiece 19 with the lips, and exhales through themouthpiece 19. Where an air flow can be established through the mainflow path 21, by virtue of the aperture 90 in the vane 89 of the triggermember 61, a bi-directional air flow is developed through the nasalcavities. As illustrated in FIG. 7( c), with continued exhalation, thepressure differential across the vane 89 of the trigger member 61increases, until such point that the pressure differential is such as tocause the rotation of the vane 89 and thereby the pivot pin 87 to whichthe vane 89 is attached. As illustrated in FIG. 7( d), where an air flowcannot be established through the nosepiece 17, for example, as a resultof nasal congestion, the pressure in the main flow path 21 increases,until such point that the pressure acts to open the sealing unit 93, inthis embodiment by driving the sealing member 97 from the annular seal95, at which point an air flow is established via the gas venting path26 and the external venting apertures 25, 25 to atmosphere, which airflow is such as to cause the rotation of the vane 89 and thereby thepivot pin 87 to which the vane 89 is attached. This rotation of thepivot pin 87 is such as to cause the movement of the link member 65 ofthe locking assembly 59, which link member 65, once no longer abuttingthe pivot pin 87 and supporting the locking assembly 59 in the lockingconfiguration, allows for the movement, under the action of the loadingunit 42, of the container 35 and the pump fitting 36 coupled thereto toactuate the substance supply unit 31 and deliver a metered volume ofliquid from the delivery tube 41 of the outlet unit 32.

FIGS. 8 and 9 illustrate a breath-actuated nasal delivery device inaccordance with a second embodiment of the present invention.

The delivery device comprises a housing unit 114 which comprises a mainbody 115, a nosepiece 117 for fitting to a nostril of a user, and amouthpiece 119 through which the user exhales to actuate the deliverydevice.

The main body 115 includes an aperture 116 for enabling any air flowthereinto to escape therefrom.

The main body 115 defines a main flow path 121 which provides a fluidcommunication path between the nosepiece 117 and the mouthpiece 119, andthrough which a substance is delivered to the nasal cavity of the user.The main flow path 121 includes an aperture 122 and an abutment 123therein, the purpose of which will become apparent hereinbelow. In thisembodiment the main flow path 121, in fluidly communicating thenosepiece 117 to the mouthpiece 119, is such that an exhalation breathof the user can provide for bi-directional flow through the nasalcavities as disclosed in WO-A-00/51672. In alternative embodiments therecould be no fluid communication path between the nosepiece 117 and themouthpiece 119 such that an exhalation breath of the user is notdirected to the nasal cavities of the user. These alternativeembodiments include those where substance is delivered in a separate gasflow, such as from a pressurized canister, for example, a pMDI canister.

In this embodiment the nosepiece 117 has a tapering section whichnarrows to the distal end thereof and acts, when inserted, typicallyfrom about 1 to 2 cm, into the anterior part of a nasal cavity, toexpand the narrow nasal valve of the nasal cavity and provide afluid-tight seal.

In this embodiment the mouthpiece 119 is configured to be gripped in thelips of a user. In an alternative embodiment the mouthpiece 119 could beconfigured to be gripped by the teeth of a user and sealed by the lipsof the user. In a preferred embodiment the mouthpiece 119 isspecifically configured to have one or both of a shape and geometrywhich allows the delivery device to be gripped repeatedly in the sameposition, thereby providing for the nosepiece 117 to be reliablyinserted in the same position in the nasal cavity.

The delivery device further comprises a breath-actuated substancedelivery assembly 124 for delivering substance through the main flowpath 121 on exhalation by the user through the mouthpiece 119.

The substance supply assembly 124 comprises a substance supply unit 125for delivering a metered dose of a substance on actuation of the same,an outlet unit 127 which is connected to the substance supply unit 125for delivering substance through the main flow path 121, a loadingmechanism 129 for loading the substance supply unit 125, and a releasemechanism 131 for releasing the substance supply unit 125 from a loaded,non-actuated position to the actuated position on exhalation by the userthrough the mouthpiece 119.

In this embodiment the substance supply unit 125, as a mechanical pump,comprises a container 133 containing a volume of liquid containing asubstance, a pump fitting 135 which includes a metering chamber and isconnected to the container 133, and an outlet stem 137 which is movablydisposed to the pump fitting 135 and through which liquid is delivered.In operation, a metered volume of liquid is delivered on relativemovement of the pump fitting 135 and the outlet stem 137, in thisembodiment movement of the pump fitting 135 in relation to the outletstem 137, between a first position, as illustrated in FIG. 8( a), inwhich the outlet stem 137 is extended from the pump fitting 135 and asecond position, as illustrated in FIG. 8( c), in which the outlet stem137 is depressed into the pump fitting 135.

In this embodiment the substance supply unit 125 is a multi-dose devicefor enabling the delivery of a succession of metered doses of substance.In an alternative embodiment the substance supply unit 125 could be asingle dose device for delivering a single metered dose of substance.

The pump fitting 135 includes at least one lug 138 which provides anabutment surface 139, as will be described in more detail hereinbelow.In this embodiment the abutment surface 139 of the at least one lug 138is an inclined surface.

The outlet unit 127 comprises an outlet block 140 which is connected tothe outlet stem 137 of the substance supply unit 125 and, in thisembodiment, includes a valve and swirl chamber, and a delivery tube 141from which a mist of fine droplets of the liquid is expelled onactuation of the substance supply unit 125. In an alternative embodimentthe delivery tube 141 could be configured to deliver a liquid jet.

The loading mechanism 129 comprises a biasing element 143, in thisembodiment a resilient element, here a compression spring, which isloaded with a predetermined force which is sufficient to actuate thesubstance supply unit 125 when released, in this embodiment by causingrelative movement of the pump fitting 135 in relation to the outlet stem137, and a loading member 145 for loading the biasing element 143. Inthis embodiment the loading member 145 comprises a lever which ismovable to a loading position, as illustrated in FIG. 8( b), in whichthe loading member 145 acts to load the biasing element 143 by biasingthe same against the bottom end of the container 133 of the substancesupply unit 125.

The release mechanism 131 comprises a locking assembly 147 which acts tolock the substance supply unit 125 in the non-actuated position, in thisembodiment by preventing movement of the pump fitting 135 relative tothe outlet stem 137, until actuation of the release mechanism 131, and atrigger member 149 which is coupled to the locking assembly 147 anddisposed at the mouthpiece 119 such as to support the locking assembly147 until acted upon by an oral exhalation breath of a user.

In this embodiment the locking assembly 147 comprises a first, supportmember 151, which is hinged, in this embodiment to the outlet block 140of the outlet unit 127, and engages the at least one lug 138 on the pumpfitting 135 in the locked position, and a second, link member 153 whichcouples the support member 151 to the trigger member 149 when loaded.

In this embodiment the support member 151 is substantially L-shaped,with one end thereof being hinged to the outlet block 140 of the outletunit 127, the other end thereof supporting the link member 153, andincluding an abutment surface 155, in this embodiment a curved surface,which engages the abutment surface 139 of the at least one lug 138 inthe locked position. In this embodiment the link member 153 is hinged tothe support member 151 such as to be freely movable between a first,locked position, as illustrated in FIG. 8( a), in which the link member153 abuts the support member 151 and defines a support position, and asecond, released position. In an alternative embodiment the link member153 could comprise a flexible, preferably resilient, element.

In this embodiment the trigger member 149 comprises a pivot pin 157about which the trigger member 149 is rotatable between a first,supporting position, as illustrated in FIG. 8( a), in which the triggermember 149 engages the locking assembly 147 in the locked position, anda second, released position, as illustrated in FIG. 8( c), in which thelocking assembly 147 is not supported and released from the lockingposition.

In this embodiment the trigger member 149 further comprises a first,flow-sensitive vane 159 which extends from the pivot pin 157 andsubstantially closes the main flow path 121 when in the supportingposition. In this embodiment the first vane 159 is configured to engagethe abutment 123 in the main flow path 121 when in the supportingposition. The provision of the abutment 123 acts to prevent theactuation of the substance supply unit 125 on inhalation by the user. Inthis embodiment the first vane 159 includes an aperture 160 which actsto require a predetermined air flow through the main flow path 121 priorto releasing the trigger member 149 from the supporting position.Advantageously, with this configuration, a bi-directional air flow canbe achieved through the nasal cavities prior to release of substancethrough the nosepiece 117.

In this embodiment the trigger member 149 further comprises a second,pressure-sensitive vane 161 which extends from the pivot pin 157 andsubstantially seals the aperture 122 in the main flow path 121 when inthe supporting position. In this embodiment the second vane 161 isconfigured such as to release the trigger member 149 from the supportingposition on the generation of a predetermined pressure in the main flowpath 121. Advantageously, with this configuration, the substance supplyunit 125 can be actuated even when the nasal cavity is so congested thatno, or not sufficient, an air flow can be achieved.

Operation of the delivery device will now be described hereinbelow.

In operation, a user first primes the device by rotating the loadingmember 145 of the loading mechanism 129 to the loaded configuration, asillustrated in FIG. 8( b). With the release mechanism 131 in the lockedposition, that is, with the abutment surface 155 of the supportingmember 151 of the locking assembly 147 abutting the abutment surface 139of the at least one lug 138 on the pump fitting 135, the biasing element143 is biased against the bottom of the container 133 of the substancesupply unit 125. The user then inserts the nosepiece 117 into one of thenasal cavities, grips the mouthpiece 119 with the lips, and exhalesthrough the mouthpiece 119. Where an air flow can be established throughthe main flow path 121, by virtue of the aperture 160 in the first vane159 of the trigger member 149, a bi-directional air flow is developedthrough the nasal cavities. With continued exhalation, the pressuredifferential across the first vane 159 of the trigger member 149increases, until such point that the pressure differential is such as tocause the rotation of the first vane 159 and thereby the pivot pin 157to which the first vane 159 is attached. Where an air flow cannot beestablished, for example, as a result of nasal congestion, the pressurein the main flow path 121 increases, until such point that the pressureacts to cause the rotation of the second vane 161 and thereby the pivotpin 157 to which the second vane 161 is attached. This rotation of thepivot pin 157 is such as to cause the movement of the link member 153 ofthe locking assembly 147, which link member 153, once no longer abuttingthe pivot pin 157 and supporting the locking assembly 147 in the lockingconfiguration, allows for the movement, under the action of the biasingelement 143, of the container 133 and the pump fitting 135 coupledthereto to actuate the substance supply unit 125 and deliver a meteredvolume of liquid from the delivery tube 141 of the outlet unit 127.

FIGS. 10 and 11 illustrate a breath-actuated nasal delivery device inaccordance with a third embodiment of the present invention.

The nasal delivery device of this embodiment is very similar to that ofthe above-described second embodiment. Thus, in order to avoidunnecessary duplication of description, only the differences will bedescribed in detail, with like parts being designated by like referencesigns.

The nasal delivery device of this embodiment differs only in that thetrigger member 149 does not include a second vane 161 as in theabove-described second embodiment, but instead comprises a resilientelement 163 which acts as a pressure-sensitive element. Operation is thesame as for the above-described embodiment, with the resilient element163 being deformed, and hence causing rotation of the pivot pin 157,with an increased pressure in the main flow path 121, such that thepivot pin 157 is rotated sufficiently to release the locking assembly147 on a predetermined pressure being developed in the main flow path121.

In alternative embodiments the trigger member 149 could be configured toinclude only a single vane 159, 161 or element 163 such that the triggermember 149 is only one of flow or pressure sensitive. In particular,where the exhalation breath of a user is not delivered to the nasalairway, that is, where the nosepiece 117 is not fluidly connected to themouthpiece 119, the trigger member 149 need only be configured to be oneof flow or pressure sensitive, since there will be no obstruction to theexhalation breath.

For example, in these embodiments the substance supply unit 125 couldcomprise an aerosol canister, such as used in a pressurized metered doseinhaler (pMDI), for delivering a propellant, preferably ahydrofluoroalkane (HFA) propellant or the like, containing a substance,preferably a medicament either as a suspension or a solution.

In other embodiments the substance supply unit 125 could comprise a drypowder delivery unit for delivering a metered dose of substance in a drypowder, either entrained in the exhalation breath of a user or in aseparate gas flow as supplied by a separate gas source.

In still yet other embodiments the substance supply unit 125 couldcomprise a nebulizer for delivering a metered dose of a nebulizedsubstance, either entrained in the exhalation breath of a user or in aseparate gas flow as supplied by a separate gas source.

In still yet also other embodiments the substance supply unit 125 couldcomprise a jet pump which delivers, in this embodiment squirts, ametered dose of a substance as a jet on actuation thereof, typically byreleasing the stored energy in a compression spring.

In these embodiments the delivery device is configured to deliver theexhalation breath through one nostril of a user such as to flow aroundthe posterior margin of the nasal septum and out of the other nostril ofthe user, thereby achieving bi-directional flow through the nasalcavities as disclosed in WO-A-00/51672.

In alternative embodiments the delivery device could be configured todeliver substance at a reduced pressure which is not sufficient toachieve bi-directional delivery through the nasal cavities. Thisnotwithstanding, these embodiments are still advantageous as compared toknown delivery devices in providing for velum closure and being capableof achieving targeted delivery. In one embodiment the delivery devicecould include two nosepieces 117 for the simultaneous delivery to eachof the nasal cavities. This embodiment advantageously provides forthree-point fixation of the delivery device via the nosepieces 117 andthe mouthpiece 119.

FIGS. 12 and 13 illustrate a breath-actuated nasal delivery device inaccordance with a fourth embodiment of the present invention.

The nasal delivery device of this embodiment is very similar to that ofthe above-described second and third embodiments. Thus, in order toavoid unnecessary duplication of description, only the differences willbe described in detail, with like parts being designated by likereference signs.

The nasal delivery device of this embodiment differs principally only inthat the substance supply unit 125 is an aerosol canister, such as usedin a pressurized metered dose inhaler (pMDI), for delivering apropellant, preferably a hydrofluoroalkane (HFA) propellant or the like,containing a substance, in that the release mechanism 131 furthercomprises a biasing element 169, in this embodiment a resilient element,for biasing the locking assembly 147 to the locking configuration, andin that the trigger member 149 comprises only a single flow-sensitivevane 159. In a preferred embodiment the aerosol canister is apressurized metered dose inhaler (pMDI), for delivering a propellant,preferably a hydrofluoroalkane (HFA) propellant or the like, containinga substance, preferably a medicament either as a suspension or asolution. Operation is the same as for the above-described second andthird embodiments.

FIGS. 14 and 15 illustrate a flow-control mechanism in accordance withan embodiment of the present invention for incorporation in the mainflow path 21, 121 between the mouthpiece 19, 119 and the trigger member61, 149 of the nasal delivery devices of the above-describedembodiments.

Where a spray pump is operated in an inclined orient, typically morethan 45 degrees, or an upside-down orient, air may be drawn into thepump fitting, causing at least in part air, and not liquid, to bepumped. This will have the effect of causing a sequence of subsequentdoses to be incomplete, and the flow-control mechanism is configuredthus to prevent a user from releasing the device in an incorrect orient.

In this embodiment, as illustrated in FIG. 14( a), the flow-controlmechanism comprises a flow channel section 171 which includes a recess173, and a ball 175 which is movably captively disposed within the flowchannel section 171 and normally, with the delivery device in anacceptable orient, rests in the recess 173 to allow an air flow from themouthpiece 19, 119 to the trigger member 61, 149, but, with the deliverydevice in an unacceptable orient, the ball 175 adopts a forward,downstream position in the flow channel section 171 to block the sameand prevent the development of an air flow therethrough which isrequired to actuate the release mechanism 34, 131. A user is most likelyto attempt to operate the device when seated with their head tiltedbackwards or in the supine position. Where the device is tiltedbackwards more than a predetermined angle, as illustrated in FIG. 14(b), the ball 175 will roll from the recess 173 into a narrower,downstream part of the flow channel section 171 and block the same,thereby preventing actuation of the release mechanism 34, 131. A morecomplex mechanism may also prevent insufflations in this position.

In this embodiment the flow-control mechanism is also configured toprevent actuation of the release mechanism 34, 131 where a user blowstoo forcefully into the device. It can be advantageous to firstestablish a certain flow through the device and into the nose beforereleasing substance. The shape and/or geometry of the flow channelsection 171 at the recess 173 allows for the passage of a certain airflow, as illustrated in FIG. 15( a), but, if the air flow becomes toohigh, the ball 175 is blown into the narrow, downstream region of theflow channel section 175, as illustrated in FIG. 15( b), blocking offthe flow channel section 171, and hence the main flow path 21, 121, andthereby preventing air flow through the main flow path 21, 121, andconsequently actuation of the device. The shape and geometry of therecess 173, the angling of the flow channel section 171 at the endregions thereof and the weight of the ball 175 can be altered todetermine the maximum permitted flow.

Also, in this embodiment, where inhalation is attempted, the ball 175will be sucked into the narrow, upstream region of the flow channelsection 171, preventing further air flow, as illustrated in FIG. 15( c).

Finally, it will be understood that the present invention has beendescribed in its preferred embodiments and can be modified in manydifferent ways without departing from the scope of the invention asdefined in the appended claims.

For example, for mechanical spray pumps, issues related to priming andloss of priming are important. Normally, when the container 35, 133 isnew, the pump must be compressed typically three to five times beforeproviding the first mist at actuation. In order to ensure that therequired priming is performed before the device is used, in onemodification a counter is included which clearly shows that the deviceis primed. The subject should be able to see that the device actuallyfires before it is used.

In another modification the device is configured to provide for manualfiring, especially in the case where a conventional container 35, 133 isused which may suck air into the tube and chamber if the container 35,133 is held in an incorrect orient. With the traditional spray pumps,the dose in the chamber tends to evaporate after some hours or days,making it necessary to re-prime the pump to enable proper function wherehaving not been used for a certain period. However, recently, a new pumpdesign has been developed which incorporates a valve, preventing thisloss of prime. Still, the problem of actuating in an upside-down orvery-tilted position remains. If actuated in this position, air may bedrawn into the tube inside the container 35, 133 instead of liquid. Thiscauses one or more of the subsequent doses to be incomplete. This mayrequire repeated re-priming to restore normal function. One solution isto provide a compliant membrane inside the container 35, 133 to preventair entering the tube. Still, this solution is more expensive and theflexible membrane inside the container 35, 133 is formed other than fromglass. To change from glass may be costly, and may hinder the uptake ofthis solution, particularly where used for medicaments. The presentmechanism, which prevents release in upside-down and very-tiltedorients, will to a large extent obviate this problem.

In the described embodiments the hinge axis of the support member 63,151 of the locking assembly 59, 147 is co-incident with the axis of thesubstance supply unit 31, 125, but the hinge axis of the support member63, 151 could be offset from the axis of the substance supply unit 31,125.

1. A breath-actuated nasal delivery pump for delivering a liquidcontaining a substance to a nasal cavity of a user.
 2. The delivery pumpof claim 1, wherein the delivery pump is a spray pump and the liquid isdelivered as a liquid spray.
 3. The delivery pump of claim 1, whereinthe delivery pump is a jet pump and the liquid is delivered as a liquidjet.